Q&A on Influenza

1. (1) Avoid going out into crowds or busy streets and refrain from going to school or work.
2. (2) Practicing “cough etiquette” as a protection against droplet infections. The main route of transmission of influenza is droplet transmission from coughing or sneezing.
   Even if infected with influenza virus,
   an infected person may not have any symptoms or he/she may only develop mild cold-like symptoms, such that he/she and the people around him/her do not suspect influenza infection. Therefore, actions such as the following are important to prevent droplet transmission:
3. (1) Practice “cough etiquette” and do not cough or sneeze on anyone,
4. (2) Wear a non-woven fabric mask to avoid transmitting virus to others when you are coughing or sneezing. When there is no mask, cover your mouth and nose with a tissue or sneeze into your upper arm and do not turn your face to others, and
5. (3) Discard the used tissue into a trash can. Wash your hands immediately when you cough or sneeze into your hands.
6. 3) You should have a good rest. Getting enough sleep is particularly important.
7. 4) Drink plenty of fluids. You can drink whatever you like, including soups and teas.
8. 5) If you start feeling sick with symptoms such as high fever or difficulty breathing, seek care early at a medical facility.

Some abnormal behaviors have been reported in children and adolescents with influenza, such as suddenly running away, trying to jump out of a room or wandering around aimlessly. It is therefore important to keep an eye on small children and adolescents with influenza when they are resting at home for at least two days after the disease onset(see Q15).

*What is a sanitary non-woven fabric mask?
“Non-woven” fabric is a fabric-like material bonded together by heat or chemical treatment, instead of weaving fibers or yarns. A mask made with such fabric is called a “non-woven” fabric mask.

(Answer) Antiviral drugs against influenza include the following antiviral drugs listed below.

• Oseltamivir phosphate (brand name: Tamiflu)
• Zanamivir (brand name: Relenza)
• Peramivir (brand name: Rapiacta)
• Laninamivir octanoate (brand name: Inavir)
• Amantadine hydrochloride (brand name: Symmetrel) (effective only for influenza A)
• Baloxavir marboxil (brand name: Xofluza)

Of note, the effectiveness of these drugs varies depending on the timing of treatment and severity of symptoms. Therefore, the decision to use or not use a medication will be determined by the physician.

When treatment of influenza with antiviral drugs is given at th appropriate timing (within 48 hours of illness onset), it can shorten the duration of fever by one to two day(s) and reduce the amount of virus excreted from the nose or pharynx. If medication is initiated after two days (48 hours) of symptom onset, the drug’s full effect cannot be expected. For the drug to work effectively, it is important to comply with the dosage regimen and duration of use.

Amantadine hydrochloride (brand name: Symmetrel) is effective only for influenza A, and most of the influenza virus have acquired resistance, so it is rarely used now.
In the context of concerns such as antiviral resistance, the Japanese Association for Infectious Diseases and the Japan Pediatric Society have proposed the following for the use of Baloxavir marboxil (brand name: Xofluza).

Reference: The Japanese Association for Infectious Diseases

Reference: Japan Pediatric Society

(Answer) Drug-resistant influenza virus is a strain of virus that antiviral drugs are no longer effective or less effective against. Such a drug-resistant virus is thought to emerge through the process of replications during which a specific genetic mutation occurs.

Drug-resistant influenza virus exhibits resistance to antiviral drugs that were originally effective. However, a drug-resistant virus with a stronger pathogenicity or transmissibility compared to other influenza viruses has not been verified. In addition, a drug-resistant influenza virus does not affect the effectiveness of influenza vaccines.

(Answer) In Japan, the National Institute of Infectious Diseases and prefectural public health institutes evaluate viruses with resistance to antiviral drugs, such as Tamiflu and Relenza, every year. Please see the website of the National Institute of Infectious Diseases for details.

National Institute of Infectious Diseases: Antiviral Resistance Surveillance in Japan

The detection rate of antiviral drug-resistant influenza viruses is approximately 1% to 10%. Most of these detected viruses are collected after treatment with antiviral drugs.

As of 2019, it has been confirmed that the rate of emergence of oseltamivir-resistant virus in influenza A (H1N1)pdm2009 is low and treatment with Zanamivir or Laninamivir against resistant strains that have been isolated is effective (see the website of the National Institute of Infectious Diseases). In influenza type B, the resistant rate towards any of the influenza antivirals is lower compared to other influenza types. Japan will continue to closely monitor the emergence of drug-resistant viruses through antiviral resistance surveillance.

(Answer)Some abnormal behaviors (suddenly running away, trying to jump out of a room, wandering around aimlessly, etc.) after taking influenza antiviral drugs have been reported. In addition, although very rare, cases of death following a fall from a building have been reported as a result of these abnormal behaviors.

The causal relationship between taking influenza antiviral drugs causes and these abnormal behaviors is unclear. However, the following facts have been reported based on the results of research to date:
・ In some patients with influenza infection, similar abnormal behaviors may appear even in the absence of taking an antiviral drug;
・ Abnormal behaviors may appear regardless of the type of influenza antiviral drugs taken.

For the above-mentioned reasons, careful attention regarding abnormal behaviors is required when a person gets influenza, regardless of the type of influenza antiviral drug taken or whether a drug was taken or not (see Q15 for specific precautions).
〔A report on the relationship between Tamiflu and abnormal behavior〕

(Answer) In some patients who have gotten influenza, abnormal behaviors have been reported regardless of the type of influenza antiviral drug taken or whether a drug was taken or not (see Q14).

When an infant or adolescent get influenza and is being taken care of at home, the guardian should take precautionary measures against accidents such as fatal falls for at least two days following fever onset, regardless of the type of influenza antiviral drug taken or whether a drug is taken or not.

It is known that serious abnormal behaviors which could cause accidents such as falling off a building appear mostly in male children and adolescents under 20 years of age, within two days of fever onset.

Examples of measures to prevent patients from accidents such as falling off a building
・ Be sure to lock the entrance door and windows in all rooms (may help to use internal and auxiliary locks if available);
・ Have the patient sleep in a room not facing a balcony;
・ Have the patient sleep in a room with barred windows (if there is one).
・ Have the patient sleep in a room on the ground floor if possible (in case of free-standing housing).

○Examples of abnormal behavior
・Suddenly standing up and attempting to leave the room.
・Opening the window and going out on the balcony in an excited state, and trying to jump off the balcony.
・Going out of the house, wandering around, and not responding even if the patient is spoken to.
・Going outside, with the patient feeling that he/she is being attacked by someone.
・Saying something strange and wandering around the room crying.

(Answer) Antibacterial drugs are not effective against influenza viruses, but elderly persons and physically weak persons are especially prone to secondary bacterial infections such as pneumococcal infection. Thus, in some cases, antibacterial drugs are administered as a treatment for complications such as bronchitis and pneumonia that are caused by coinfection with a bacteria or virus.

(Answer)In general, it is believed that influenza viruses are released from the nose or throat for about three to seven days after the disease onset. So, during this shedding period, it is necessary to avoid going out during this period.

Although the amount of viruses released decreases as the fever abates, viruses are still thought to be released even after the fever subsides. The duration of viral shedding varies by individual; however, while symptoms such as coughing or sneezing persist, it is advisable to take sufficient care not to transmit influenza to others by wearing a medical/surgical mask, etc.

The School Health and Safety Act (Act No. 56 of 1958) defines the period of suspension from school attendance for influenza as “five days after symptom onset and two days (three days for infants) after defervescence (when you no longer have a fever) However, this does not apply if a school doctor or any other physician determines that there is no risk of infection.

(Answer) Diagnosis and treatment decisions are made by the physician who examines the patient, based on a comprehensive evaluation of the patient’s physical symptoms, test results, and other medical findings.
It is not advisable for workplaces to require employees to provide a certificate of cure or a negative test result because of the difficulty in proving a negative test result for influenza. There is also the risk in potentially overburdening health care facilities through this requirement.

(Answer) According to the "Explanation of Preventable Infectious Diseases in Schools (Published March 2018)", "the diagnosis is based on the medical knowledge of the physician who examined the patient and there is no need for a standard requirement from the school to perform certain tests for all children. The same is true for the determination of cure (certificate of cure). "

According to the Guidelines for Infectious Disease Control in Daycare Centers (2018 Revision), "the decision for whether a child is fully recovered and permitted to return to school including group activities, is made by the physician who examines the child based on medical knowledge, taking into account the overall physical symptoms and other laboratory results. Regarding the treatment of a child who has been diagnosed with an illness and who has resumed attending preschool, it is important to consult with local and prefectural medical institutions, medical associations, schools, etc., with the support of the municipality, taking into account the burden on the child and the length of medical treatment for each situation. As a result of these consultations, it is considered that the parents or guardians may submit a "written opinion (doctor's statement)" or "registration form" (completed by the parents) to the nursery, depending on the type of disease.

(Answer)

1. (1)In principle, one dose of vaccination is given for individuals aged 13 years and older. (Note 1). Although the package insert of influenza vaccines states to use “one or two doses for people aged 13 years and older”, one dose of 0.5 mL influenza vaccine is reported to achieve an increase in antibody titer equivalent to two doses of vaccine (Note 2) based on research in healthy adults and persons with underlying diseases (chronic diseases) *1, 2. However, for individuals with some medical reasons where a physician judged these individuals to require two doses, two-dose regimen is an option (Note 1). Note that one dose is given as a routine vaccination under the Immunization Act in Japan (Note 3).
2. (2)Two (2) doses are given for individuals younger than 13 years of age. Since a higher increase in the antibody titer is obtained after two doses of vaccination than after one dose, the following amount and time of doses for influenza vaccine are specified in Japan. Note that persons aged 12 years at the first dose and 13 years at the second dose can be considered as 12 years of age in the following category and receive the second dose.
   
   • (i) Persons aged at least 6 months and under 3 years: 2 doses of 0.25 mL/dose (Note 4)
   • (ii) Persons aged at least 3 years and under 13 years: 2 doses of 0.5 mL/dose
3. (3)Regarding the situation in other countries, the World Health Organization (WHO) considers that “a single dose of the vaccine” is the appropriate dosage of influenza vaccine (limited to inactivated vaccines) for schoolchildren aged 9 years and over and for healthy adults. The Advisory Committee on Immunization Practices in the United States (US-ACIP) also recommends that all persons aged 9 years and older (other than “children aged 6 months to 8 years”) should receiv “1 dose” of influenza vaccine.

1. (Note 1) Persons aged 13 years and older with an underlying disease (chronic disease) who are considered to have significant immunosuppressive conditions may receive 2 doses at the physician’s discretion.
2. (Note 2) An antibody titer is the amount of antibody that can react with an antigen and the value is obtained by measuring the amount of antibody produced in the human body against viral infection or vaccination.
3. (Note 3) For eligible persons for routine influenza vaccination, see Q28..
4. (Note 4) Regarding item (2) (i) above, the condition of “Children aged at least 1 year and under 3 years: 2 doses of 0.25 mL/dose” applies to some vaccines.

1. ^*1. “Analytical Epidemiology Research on the Effectiveness and Safety of Vaccines for Vaccination” (Chief Research Officer: Yoshio Hirota (Osaka City University), the Health and Labor Sciences Research Grant on Emerging and Re-emerging Infectious Diseases from the Japanese Ministry of Health, Labour and Welfare, FY2011
2. ^*2. “Analytical Epidemiology Research on Assessment of the Effectiveness and Safety of Vaccine and Application of Measures for VPD (vaccine preventable diseases),” (Chief Research Officer: Yoshio Hirota (College of Healthcare Management)), the Health and Labour Sciences Research Grant on Emerging and Re-emerging Infectious Diseases and Immunization Policy Promotion of the Japanese Ministry of Health, Labour and Welfare, FY2016.

(Answer) When a person contracts influenza, it begins by the influenza virus entering the body through the mucosal membranes of the mouth, nose or eyes. The virus then invades a cell and replicates. This condition is referred to as “infection,” and the vaccine has limited effectiveness to completely prevent infection itself.
When the viruses increase, symptoms of influenza such as fever and sore throat appear after an incubation period of a few days. This condition is referred to as “disease onset (or having symptomatic infection).” A certain degree of effectiveness in preventing this “onset of disease” is confirmed with influenza vaccines, but the effectiveness cannot be expected to be as high as those seen with measles or rubella vaccines. After the onset of influenza, many people recover within approximately one week, but some people may have severe complications such as pneumonia or encephalopathy, leading to hospitalization or death. This is referred to as “severe” influenza. People with underlying diseases and elderly persons are at an increased risk of having “severe” influenza. The most important effect that influenza vaccines can have is to prevent this “severe” infection. A study conducted in Japan showed that vaccination effectively prevented the onset of influenza by 34-55% and deaths by 82% among elderly persons aged 65 years and older living in nursing homes ^*1.

The “effectiveness of influenza vaccines” is indicated by an index that shows “how much the risk of getting influenza is reduced in vaccinated people relative to the risk in the unvaccinated people,” based on studies in human subjects. The influenza vaccine’s effectiveness in preventing the symptomatic influenza was reported as 60% in a study conducted during the 2015/16 season among children under 6 years of age *2. A “vaccine effectiveness of 60% in preventing symptomatic influenza” is equivalent to the following condition:

• ・ Assuming that 30 of 100 unvaccinated people develop influenza (risk of symptomatic influenza is 30%),
• ・ and 24 of 200 vaccinated people develop influenza (risk of symptomatic influenza is 12%),

→ Vaccine effectiveness =｛（30 -12）/ 30｝x 100 = (1 - 0.4) x 100 = 60%

The risk of symptomatic influenza in vaccinated people is reduced by 60% relative to the risk in unvaccinated people. This means that 60% of those who developed influenza among unvaccinated persons (18 of 30 people in the above scenario) could have avoided the onset of influenza if they had been vaccinated.
Current influenza vaccines do not ensure that people will never develop influenza if they receive the vaccination. However, the vaccine is considered to have a certain degree of effectiveness in preventing symptomatic influenza, as well as severe infection and death after the onset of disease.

1. ^*1. “Research on the Effectiveness of Influenza Vaccine” (Chief Research Officer: Hitoshi Kamiya (National Mie Hospital), supported by the Health and Labour Sciences Research Grant for Research on Emerging and Re-emerging Infectious Diseases of the Japanese Ministry of Health, Labour and Welfare, FY1999
2. ^*2. “Analytical Epidemiological Research on Assessment of the Effectiveness and Safety of the Vaccine and Application of Measures for VPD (vaccine preventable diseases)”, (Chief Research Officer: Yoshio Hirota (College of Healthcare Management)), supported by a Health and Labour Sciences Research Grant for Research on Emerging and Re-emerging Infectious Diseases and Immunization Policy Promotion of the Japanese Ministry of Health, Labour and Welfare, FY2016.

(Answer) Influenza vaccines are manufactured based on the viruses that are predicted to circulate during the upcoming season. Therefore, it is recommended that people who had an influenza vaccination the previous year also receive an influenza vaccination in the present year.

(Answer)Inactivated influenza vaccines used currently in Japan do not have the ability to prevent infection completely, but are effective to a certain extent in preventing symptomatic influenza, along with severe infection or death following onset of influenza.

As for the effectiveness of influenza vaccine in infants, although varying somewhat by report, the vaccine effectiveness has generally been reported as 20-60% in preventing symptomatic infection.* There are also some reports indicating effectiveness in preventing severe influenza in infants. (Source: Katayose et al. Vaccine. 2011 Feb 17;29(9):1844-9)

In order to protect infants from influenza virus infection, it is advisable for families and adults around infants to try to reduce the chances of infants becoming exposed to influenza virus as much as possible--by practicing strict hand washing and cough etiquette, as well as by avoiding places where a lot of people gather during the peak influenza period.

1. ^*1.“Research on Effectiveness of Influenza Vaccine in Infants” (Chief Research Officer: Hitoshi Kamiya (National Mie Hospital) and Masaro Kaji (Kurume University), the Health and Labor Sciences Research Grant on Emerging and Re-emerging Infectious Diseases from the Japanese Ministry of Health, Labour and Welfare, FY2002
2. ^*2. “Analytical Epidemiology Research on Assessment of Effectiveness and Safety of Vaccine and Application of Measures for VPD (vaccine preventable diseases)”, (Chief Research Officer: Yoshio Hirota (College of Healthcare Management)), the Health and Labor Sciences Research Grant on Emerging and Re-emerging Infectious Diseases and Immunization Policy Promotion from the Japanese Ministry of Health, Labour and Welfare, FY2016.

(Answer) Influenza vaccines are manufactured using embryonated eggs. Egg-adaptation is necessary so that viruses can easily grow in an egg. The egg-adaptation is a process whereby a virus adapts to the environment in the egg through successive cultivation. However, genetic mutation of viruses occurs during adaptation. When any genetic mutation occurs, the difference in the degree of the effects on immunity (difference in antigenicity) may be observed between the actual circulating influenza virus (circulating strain) and the influenza virus used for vaccine development (vaccine strain). However, even in such cases, epidemiological studies show that a certain degree of effectiveness is maintained in humans. This is thought to be the case because humans are considered to have certain amount of cross-reactive antibodies due to yearly exposure to influenza viruses, which is not the case for the experimental animals used for research on influenza viruses.

(Answer) The Influenza vaccine now broadly used in Japan is called “quadrivalent vaccine,” because the vaccine is manufactured by incubating each of the influenza A viruses (H1N1 and H3N2 strains) and influenza B viruses (Yamagata and Victoria lineages).

(Answer) The influenza season in Japan is generally between December and April every year and peaks from late January to early March. Therefore, it is desirable to receive the vaccine before mid-December.

(Answer)Vaccine is expected to be supplied at approximately the same level as delivered to hospitals and clinics before the 2019/2020 season (Note 1).

The Japanese Government asks healthcare professionals and wholesalers for the appropriate use of the vaccine, per below:
• Iterate that individuals aged 13 years and older should receive 1 dose, unless determined by a physician that an individual requires 2 doses (Note 2) (Note 3)
• Ensure that the volume of vaccines purchased are appropriate and deemed necessary (refrain from ordering the vaccine unnecessarily early or in unnecessarily large amounts, etc.)

1. (Note 1) The expected amount of supply in this season (as of October 2021) is approximately 28,180,000 vials. Note that 1 vial contains a sufficient amount of vaccine solution for 2 healthy adults.
2. (Note 2) People aged 13 years and older with underlying diseases (chronic diseases) who are considered to have significant immunosuppression may have to receive 2 doses at the physician’s discretion.
3. (Note 3) See also Q20.

(Answer) There are some influenza vaccine formulations with enough medicinal solution filled in one vial for multiple doses. Regarding this type of product, the package insert describes that, once a vial is opened, the content of the vial should be used during the same day. Please pay attention to the expiration date of the product and precautions pertaining to the vaccine, and use within 24 hours after opening.

(Answer) The National Health Insurance does not cover influenza vaccination because the vaccine is not used to treat disease. In principle, you must pay the full fee and the cost differs by medical institution.

However, those eligible for routine vaccination under the Immunization Act (Law Number 68 of 1948) may receive government support for the medical expenses associated with influenza vaccine. Please ask about it at your local municipal office (health center), medical association, healthcare facility, or your family doctor (some local governments provide their own financial support schemes even for those who are not eligible for routine vaccination).

(Answer) Those who are in the following categories below are eligible for routine vaccination for influenza because they are at higher risk of severe influenza and may benefit greatly from vaccination. If you are thinking about receiving the flu vaccine, please make a decision upon consultation with your doctor.

(Answer) You can receive the influenza vaccine(s) at a local medical institution or at a family doctor’s office and the cost and immunization period vary depending on the municipality. Please contact the municipal office of your residence (health center), medical association, medical facility, or your family doctor, etc. for information on medical facilities that provide influenza vaccines and relevant measures in the community.

(Answer) Even though it is a routine vaccination, it does not mean you are guaranteed to receive routine vaccination against influenza. A person falling under any of the following categories may not be suitable for immunization or must take due care when receiving a vaccine.

Those who are not suitable for vaccination (Implementation Regulations on Immunization: Ordinance of the Ministry of Health and Welfare No. 27, September 17, 1958. (Latest revision: Ordinance of the Ministry of Health, Labour and Welfare No. 5, January 17, 2020)):

• Persons with fever
• Persons who are in an acutely critical condition
• Persons with a history of anaphylaxis due to the vaccine components
• Persons with a past history of fever within two days of influenza vaccination or those who have developed symptoms indicative of allergic reactions such as systemic eruptions
• Any other persons who are not in a suitable condition to receive the vaccine

Persons requiring precautions when making vaccination decisions (Implementation Guidelines for routine immunization: “Implementing Immunizations based on the provisions of Article 5, paragraph 1 of the Immunization Act” (Notice of the Director of Health Bureau, Ministry of Health, Labour and Welfare No. 5, Issuance Number 0204 of Health Bureau February 4, 2020 [Annex]).(Please check the descriptions):

• (A)Persons with underlying diseases, such as cardiovascular diseases, renal diseases, hepatic diseases, hematological diseases, or developmental disorders.
• (B)Persons with a history of convulsion(s)
• (C)Persons who have been diagnosed as having immunodeficiency, and persons whose close relatives are diagnosed as having congenital immunodeficiency
• (D)Persons who may be at risk of having allergic reactions to vaccine components

The Ministry of Health, Labour and Welfare (MHLW) has established the “Consultation Desk for Infectious Diseases/Vaccinations” in order to accurately respond to questions such as general preventive measures and current epidemic situations of infectious diseases, including influenza, as well as regarding the significance, effectiveness, and adverse events of vaccination.
[Consultation Desk for Infectious Diseases/Vaccination]
Telephone: 0422-70-1485(from 9 a.m. to 5 p.m. ^*excluding Saturday, Sunday, holidays & year-end and New year holidays)
^* We do not respond to opinions/questions regarding the government.
^*The Ministry of Health, Labour and Welfare has assigned an external company to provide the services of the consultation desk.